PROJECT ABSTRACT Opioid use disorders (OUDs) in pregnancy are a US public health crisis; current standard of care is treatment with an opioid agonist such as buprenorphine (BPH), shown to improve pregnancy outcomes however with an associated risk for neonatal abstinence syndrome (NAS) and possible long-term neurodevelopmental consequences. The opioid antagonist naltrexone represents a novel treatment option for OUD in pregnancy which would not expose the developing fetus to opioids, greatly reducing the risk for NAS and potentially improving maternal and infant outcomes. Preliminary animal and human studies demonstrate minimal impact on pregnancy and fetal outcomes with naltrexone exposure, however there is an overall lack of prospective human data fully evaluating safety, efficacy, and the full-range of maternal and infant outcomes. In addition, the pharmacokinetics, pharmacogenomics, placental transfer, breast milk transfer and safety of naltrexone when used during pregnancy and the postpartum period are unknown. We propose to fill these gaps in knowledge by studying the safety, efficacy, pharmacokinetics, and pharmacogenomics of naltrexone for pregnant women with OUDs, evaluating comprehensive mother-infant outcomes throughout the pregnancy and first year after birth. We will enroll 50 pregnant women stabilized pre-pregnancy on extended-release naltrexone (XR-NTX) and 50 comparison women on BPH from Boston Medical Center and the University of North Carolina in this multi-centered prospective comparative cohort study. The specific aims of this project are: 1) Safety and Efficacy: To compare maternal outcomes (safety, relapse, retention in care), fetal outcomes (growth, fetal distress), and infant outcomes (NAS, growth, neurodevelopment) during pregnancy until 12 months post- delivery; 2) Pharmacokinetics: To determine the pharmacokinetics of XR-NTX in pregnant and postpartum women; 3) Genomics: To examine the association between genetic variants and epigenetic modification in the mu-opioid receptor (OPRM1) gene, as well as global DNA methylation changes after treatment with XR-NTX and BPH within the mother, placenta, and infant; and 4) Breast milk: To measure breast milk concentrations of XR-NTX and corresponding infant relative dose to determine safety for lactating women. We hypothesize that XR-NTX will be demonstrated to be a safe and effective treatment option for pregnant and postpartum women with OUD, with improved maternal and infant outcomes in comparison with opioid agonist treatment. The results of this study hold the promise to guide planned future studies examining the use of both XR-NTX and other agonist medications in the context of best practice treatment for OUD in pregnancy in order to improve long-term maternal and infant outcomes.